Cerebral Palsy Among Term and Postterm Births

Dag Moster; Allen J. Wilcox; Stein Emil Vollset; et al.

JAMA. 2010;304(9):976-982 (doi:10.1001/jama.2010.1271) Online article and related content current as of September 29, 2010. http://jama.ama-assn.org/cgi/content/full/304/9/976

Supplementary material eTable and eFigures http://jama.ama-assn.org/cgi/content/full/304/9/976/DC1 Correction Contact me if this article is corrected. Citations This article has been cited 1 time. Contact me when this article is cited. Topic collections Neurology; Movement Disorders; Pediatric Neurology; Neurology, Other; Pediatrics; Congenital Malformations; Neonatology and Infant Care; Women's Health; Pregnancy and Breast Feeding Contact me when new articles are published in these topic areas. CME course Online CME course available. Related Articles published in Cerebral Palsy the same issue Janet M. Torpy et al. JAMA. 2010;304(9):1028.

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Cerebral Palsy Among Term and Postterm Births

Dag Moster, MD, PhD Context Although preterm delivery is a well-established risk factor for cerebral palsy Allen J. Wilcox, MD, PhD (CP), preterm deliveries contribute only a minority of affected infants. There is little Stein Emil Vollset, MD, DrPH information on the relation of CP risk to gestational age in the term range, where most CP occurs. Trond Markestad, MD, PhD Objective To determine whether timing of birth in the term and postterm period is Rolv Terje Lie, PhD associated with risk of CP. EREBRAL PALSY (CP) IS THE Design, Setting, and Participants Population-based follow-up study using the most common cause of physi- Medical Birth Registry of Norway to identify 1 682 441 singleton children born in the cal disability in childhood, years 1967-2001 with a gestational age of 37 through 44 weeks and no congenital with limitations that persist anomalies. The cohort was followed up through 2005 by linkage to other national registries. throughoutC life.1-3 Cerebral palsy is characterized by nonprogressive dis- Main Outcome Measures Absolute and relative risk of CP for children surviving orders of movement and posture, pre- to at least 4 years of age. sumed to result from insult to the brain Results Of the cohort of term and postterm children, 1938 were registered with CP during fetal or early infant life.4 These in the National Insurance Scheme. Infants born at 40 weeks had the lowest risk of CP, motor problems are often accompa- with a prevalence of 0.99/1000 (95% confidence interval [CI], 0.90-1.08). Risk for nied by disturbances of cognition and CP was higher with earlier or later delivery, with a prevalence at 37 weeks of 1.91/ 1,3,4 1000 (95% CI, 1.58-2.25) and a relative risk (RR) of 1.9 (95% CI, 1.6-2.4), a preva- other neurologic difficulties. Cere- lence at 38 weeks of 1.25/1000 (95% CI, 1.07-1.42) and an RR of 1.3 (95% CI, 1.1- bral palsy can be a severe disability and 1.6), a prevalence at 42 weeks of 1.36/1000 (95% CI, 1.19-1.53) and an RR of 1.4 a substantial burden for the affected in- (95% CI, 1.2-1.6), and a prevalence after 42 weeks of 1.44 (95% CI, 1.15-1.72) and dividual’s family and society. an RR of 1.4 (95% CI, 1.1-1.8). These associations were even stronger in a subset The underlying causes of CP re- with gestational age based on ultrasound measurements: at 37 weeks the prevalence main largely unknown.5 Cerebral palsy was 1.17/1000 (95% CI, 0.30-2.04) and the relative risk was 3.7 (95% CI, 1.5-9.1). is associated with complicated labor and At 42 weeks the prevalence was 0.85/1000 (95% CI, 0.33-1.38) and the relative risk delivery, but most cases have little ap- was 2.4 (95% CI, 1.1-5.3). Adjustment for infant sex, maternal age, and various so- parent association with delivery care.6,7 cioeconomic measures had little effect. One of the strongest predictors of CP Conclusion Compared with delivery at 40 weeks’ gestation, delivery at 37 or 38 is preterm birth, with the risk of CP in- weeks or at 42 weeks or later was associated with an increased risk of CP. creasing steadily with earlier deliv- JAMA. 2010;304(9):976-982 www.jama.com ery.8 Although risk is lower among term births, about three-fourths of all in- plored the relation of CP risk with ges- METHODS fants with CP are born after 36 weeks.8 tational age among term and postterm Study Cohort Within this range of term births, there births using national health and insur- Each Norwegian citizen has a unique are few data on the possible associa- ance registries in Norway. identification number that allows link- tion of CP with gestational age. We ex- Author Affiliations: Department of Public Health National Institutes of Health, Durham, North Caro- and Primary Health Care (Drs Moster, Vollset, and lina (Dr Wilcox); and Medical Birth Registry of Nor- See also Patient Page. Lie) and Department of Clinical Medicine, Section way, Norwegian Institute of Public Health, Bergen for Pediatrics (Dr Markestad), University of Bergen, (Drs Vollset and Lie). CME available online at Bergen, Norway; Department of Pediatrics, Hauke- Corresponding Author: Dag Moster, MD, PhD, De- www.jamaarchivescme.com land University Hospital, Bergen, Norway (Drs partment of Public Health and Primary Health Care, and questions on p 1019. Moster and Markestad); Epidemiology Branch, University of Bergen, PO Box 7804, N-5020 Bergen, National Institute of Environmental Health Sciences, Norway ([email protected]).

Downloaded from www.jama.com at University of Alabama-Birmingham on September 29, 2010 CEREBRAL PALSY AND TIMING OF BIRTH age of an individual’s data among the ably diagnosed.16,17 Most cases are Figure 1. Prevalence of Cerebral Palsy and national registries. The Medical Birth established by 4 years, and so we Daily Number of Births by Gestational Age Registry of Norway has collected in- required our cohort to survive and be formation since 1967 on all births with followed up to at least the age of 4 3.5 Daily Prevalence a gestational age of at least 16 weeks.9 years. Information on deaths was 3.0 Information on gestational age is based obtained through the Cause of Death 2.5 on the last menstrual period (LMP). Registry. Information on parents’ 2.0

Using the birth registry, we identified education and immigration status 1.5

all singleton live births from 1967 came from the Norwegian National of Prevalence 1.0

through 2001 with a gestational age of Education Database and Statistics Palsy/1000 Cerebral 37 to 44 weeks. Follow-up data were Norway.18 0.5 0 available through 2005. To remove The study was approved by the 37 38 39 40 41 42 43 44 45 likely errors of gestational age based on Norwegian Data Inspectorate, the Gestational Age, wk LMP, we excluded infants with birth Norwegian Labor and Welfare Orga- weights more than 3 standard devia- nization, the Office of the National 80 000 Daily No. of Births tions from the mean for a given gesta- Registrar, and the Norwegian Direc- 60 000 tional-age week, stratified by infant torate of Health. The approval in- sex.10 Birth defects are associated with cluded a waiver of individual study 40 000 CP and also with gestational age at participant consent. birth.11 To help remove possible con-

No. of Live Births 20 000 founding by birth defects, we also ex- Statistical Analyses cluded infants with any registered con- We first estimated the prevalence of CP 0 genital anomalies. Birth defects were according to gestational day of birth for 37 38 39 40 41 42 43 44 45 coded using International Classifica- all births from 37 to 44 weeks. In fur- Gestational Age, wk tion of Diseases (ICD) versions 8 and 10 ther analyses, we categorized gesta- Prevalence of cerebral palsy/1000 (top panel) and daily in the Medical Birth Registry and ver- tional age into 7 groups: 37 weeks (ie, number of births (bottom panel) according to gestational age at birth from 37 weeks to 44 weeks among sions 9 and 10 in the insurance 259 to 265 days), 38 weeks, 39 weeks, the 1 682 441 members of the study cohort. The registry.12 40 weeks, 41 weeks, 42 weeks, and 43 smoothed curve (top panel) was fitted using the lo- Cerebral palsy cannot be diagnosed through 44 weeks. Ratios of preva- cally weighted scatterplot smoothing (LOESS) method. at birth. Our data on CP came from the lences were used to estimate relative Norwegian compulsory health insur- risks (RRs), with 40 weeks as the ref- for the subset of infants born since De- ance system.13 Individuals in Norway erence. We estimated the RR of CP for cember 1998. are entitled to benefits for a disability each gestational group using log- Year of birth, mother’s level of edu- that involves significant expenses, re- binomial regression and adjusted for cation, and father’s level of education quires special attention or nursing, or year of birth, sex, maternal age, single were entered as continuous variables; reduces working capacity by at least motherhood, mother’s level of educa- the remaining were categorical. Mater- 50%.14 These benefits are provided tion, father’s level of education, and im- nal age was divided into 3 categories without regard to income or wealth and migrant status of the parents. We plot- (Ͻ18 years, 18-39 years, and Ն40 are considered to provide a fairly com- ted the association of gestational age years). Father’s and mother’s educa- plete registry of disabled individuals in with congenital anomalies and dis- tion was defined on a 9-level scale, Norway. eases of the digestive system that are un- with 0 for no education and 8 (the Benefits are based on physician di- likely to be caused by time of delivery highest) for a doctoral degree. A child agnosis, with diagnoses registered ac- to explore the possibility of reverse cau- was considered to have immigrant cording to ICD-9 or ICD-10.Weob- sation or selection. parents if both parents were born out- tained information on CP (ICD-9 codes: Date of LMP is an error-prone mea- side of Norway. Since changes in CP 342-344; ICD-10 codes: G80-G83) sure of gestational age.19 Since at least prevalence and gestational–age distri- using the medical diagnoses linked to 1994, an estimated 98% of pregnant bution over the 35 years of the study the disability benefits defined previ- women in Norway have received a rou- might have affected our results, we ously. A validation study15 has shown tine ultrasound examination by the repeated the analyses in 3 smaller time that registered CP diagnoses corre- mid-second trimester.20 These data have windows (1967-1977, 1978-1989, and spond well with medical records, with been reported in the Medical Birth Reg- 1990-2001). some underregistration of the mildest istry starting in December 1998. We ex- SPSS version 17.0 was used for sta- cases. plored the quality of LMP data by re- tistical analyses (SPSS Inc, Chicago, Il- There is controversy regarding the peating the overall analysis using linois). All tests were 2-sided with a 5% youngest age at which CP can be reli- ultrasound measures of gestational age significance level.

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delivery, with a summary smoothed (Figure 2; supplementary data in Figure 2. Adjusted Relative Risks of Cerebral Palsy, Congenital Anomalies, and curve. There were 1938 individuals eTable, available at http://www.jama Digestive Diseases subsequently registered with CP .com). (1.15/1000 births; 95% confidence Ultrasound-based measurements of Cerebral palsy 2.5 interval [CI], 1.10-1.20). Delivery at gestational age were available for the 2.0 40 weeks was associated with lowest subset of 139 976 children born in

1.5 CP risk (prevalence, 0.99/1000; 95% December 1998 and later, including CI, 0.90-1.08). Compared with deliv- 85 with CP. Among this subgroup, Adjusted

Relative Risk 1.0 ery at 40 weeks, prevalence of CP at the pattern of CP risk with gestational 0.8 37 weeks was 1.91/1000 (95% CI, age was stronger with ultrasound- > 37 38 39 40 41 42 42 1.58-2.25) and RR was 1.9 (95% CI, based gestational age than with LMP 1.6-2.4); the prevalence at 38 weeks (FIGURE 3). Compared with infants Congenital anomalies 2.5 was 1.25/1000 (95% CI, 1.07-1.42) born at 40 weeks (prevalence, 0.36/ 2.0 and RR was 1.3 (95% CI, 1.1-1.6); 1000; 95% CI, 0.18-0.54), infants 1.5 the prevalence of CP at 42 weeks was born at 37 weeks had a CP preva- 1.36/1000 (95% CI, 1.19-1.53) and lence of 1.17/1000 (95% CI, 0.30- Adjusted

Relative Risk 1.0 RR was 1.4 (95% CI, 1.2-1.6); and 2.04) and RR of 3.7 (95% CI, 1.5- 0.8 after 42 weeks, the prevalence was 9.1), while infants at 42 weeks had a 37 38 39 40 41 42 >42 1.44 (95% CI, 1.15-1.72) with RR of CP prevalence of 0.85/1000 (95% CI, 1.4 (95% CI, 1.1-1.8) (FIGURE 2). 0.33-1.38) and RR of 2.4 (95% CI, Digestive diseases 2.5 TABLE 1 and TABLE 2 show charac- 1.1-5.3), based on ultrasound dating 2.0 teristics of the parents, infants, and of gestational age. 1.5 deliveries for children with and with- The prevalence of CP among births

Adjusted out subsequent CP. Children with from 37 weeks onward decreased from Relative Risk 1.0 CP were slightly more likely to have 1.4/1000 (95% CI, 1.3-1.5) in 1967- 0.8 37 38 39 40 41 42 >42 single mothers (P=.03) and parents 1971 to 0.7/1000 (95% CI, 0.6-0.8) in Gestational Age, wk with less education (PϽ.001). Com- 1997-2001 (eFigure 1). The associa- plications of labor and delivery tion of CP with gestational age, how- Information on cerebral palsy and digestive diseases (International Classification of Diseases, Ninth Revi- (breech presentation, cesarean deliv- ever, was consistent over time (eFig- sion [ICD-9] codes: 520-579, ICD-10 codes: K00- ery) were up to twice as likely for ure 2). K93) is from the study cohort of 1 682 441, whereas information on congenital anomalies is based on infants who were later diagnosed 1 720 443 (original study cohort without exclusion of with CP (PϽ.001). Boys were over- COMMENT congenital anomalies). Error bars indicate 95% con- represented among CP children Much attention has been given to fidence intervals. Reference category for all plots is 40 weeks. (P Ͻ .001). Children with CP had the high risk of CP with preterm lower mean birth weight (3437 g vs delivery.21-25 The risk of CP among 3585 g; PϽ.001) and smaller head term infants is much lower, but none- RESULTS circumference (35.1 cm vs 35.3 cm; theless most CP occurs among term There were 2 024 215 live births in Nor- PϽ.001). Children with CP were 82 deliveries. Furthermore, the risk at way from 1967 through 2001. We ex- times more likely to have had an term and beyond is not uniform. The cluded those missing data on gesta- Apgar score below 4 (PϽ.001) and risk of CP is lowest at 40 weeks, with tional age (6.0%), those born preterm were 8 times more likely to have the highest risks at 37 weeks and at 42 (5.5%), those with gestational age more been transferred to a pediatric unit weeks or later. A recent report sup- than 44 weeks (1.0%), those whose after delivery (P Ͻ .001). Most of ports our finding of increased CP risk birth weights were incompatible with these associations were present at among postterm births.16 Other neuro- their gestational age (0.7%), twins or each gestational age of delivery. logic conditions have also been found other multiple births (1.3%), those with Adjustment for year of birth, to vary by gestational age at term. A malformations recorded either in the infant sex, maternal age, presence or U-shaped pattern for low IQ was birth registry or the insurance registry absence of a partner, educational recently reported among term and (2.0%), and those who died younger level of the mother and father, and postterm births.26 than 4 years of age (0.4%). This left an immigrant status of the parents pro- Our findings do not appear to be analysis cohort of 1 682 441 singleton duced identical RRs by gestational due to errors in LMP. The U-shaped births with a gestational age of at least age (Figure 2). Congenital malforma- risk was even stronger among the 37 weeks. tions had a weak U-shaped associa- subgroup with ultrasound measures FIGURE 1 shows the distribution of tion with gestational age, while dis- of gestational age (which are still these births by gestational day at eases of the digestive system did not imperfect, but with less error than

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LMP).19 Such a strengthening of Causal Interpretation not caused by the timing of delivery, effect would be expected if the asso- Cerebral palsy risk has a robust the most plausible explanation is ciation with gestational age were true U-shaped association with gesta- reverse causation; malformed infants but blunted by measurement error tional age among infants reaching experience disruptions in their time of related to LMP. term. The biological mechanisms delivery, with increased chance of We had information on several that underlie this association are not delivery either earlier or later than 40 parental and birth characteristics as clear. One possible interpretation weeks. associated with a subsequent diagno- is that delivery too early or too late, Although the forces that regulate tim- sis of CP. These risk factors are con- even within the limited range of term ing of a normal delivery are poorly un- sistent with results from other and postterm births, increases the derstood,32,33 it appears that the types studies.15,27-31 The distribution of risk of CP. of malformations most likely to dis- these risk factors across 37- to However, an equally plausible inter- rupt the timing of delivery often in- 44-week births was generally similar pretation is that fetuses predisposed to volve cerebral function. For example, for the CP and non-CP group. CP have a disturbance in the timing of anencephalic fetuses have a tendency Adjustment for parental characteris- their delivery, which causes them to to be born postterm,34,35 children with tics had no influence on the results. be more often delivered early or late. Trisomy 18 to be born preterm or post- We did not adjust for circumstances This apparently happens with other term,36 and children with Down syn- of labor, delivery, or neonatal period fetal conditions: there is a U-shaped drome to be born early.37 It is possible because these may be part of the pattern in the risk of congenital that the cerebral damage later ex- causal pathway or an early expres- anomalies with gestational age after 37 pressed as CP similarly disrupts time sion of CP. weeks. Since congenital anomalies are of delivery.

Table 1. Parental Characteristics of the CP and Non-CP Cases Stratified by Gestational Age at Birth Weeks, No. (%) P Overall 37 38 39 40 41 42 Ն43a Valueb Total No. With CP 1938 123 193 376 486 417 248 95 Without CP 1 680 503 64 160 154 435 341 035 488 999 384 037 181 757 66 080 CP/1000 1.15 1.91 1.25 1.10 0.99 1.08 1.36 1.44 Crude RR 1.9 (1.6-2.4) 1.3 (1.1-1.5) 1.1 (1.0-1.3) 1 1.1 (1.0-1.2) 1.4 (1.2-1.6) 1.4 (1.2-1.8) (95% CI) [Reference] Maternal age at birth Ͻ18 y With CP 28 (1.4) 1 (0.8) 2 (1.0) 6 (1.6) 7 (1.4) 7 (1.7) 5 (2.0) 0 .36 Without CP 20 458 (1.2) 1035 (1.6) 1943 (1.3) 3663 (1.1) 5487 (1.1) 4547 (1.2) 2598 (1.4) 1185 (1.8) Ն40 y With CP 30 (1.5) 1 (0.8) 2 (1.0) 14 (3.7) 6 (1.2) 5 (1.2) 0 2 (2.1) .58 Without CP 23 533 (1.4) 1384 (2.2) 3296 (2.1) 5733 (1.7) 6574 (1.3) 4308 (1.1) 1654 (0.9) 584 (0.9) Single mother With CP 212 (10.9) 15 (12.2) 17 (8.8) 40 (10.6) 54 (11.1) 47 (11.3) 28 (11.3) 11 (11.6) .03 Without CP 159 054 (9.5) 7107 (11.1) 14 863 (9.6) 29 572 (8.7) 42 634 (8.7) 36 738 (9.6) 19 750 (10.9) 8390 (12.7) Level of mother’s education, mean (SD)c With CP 3.6 (1.5) 3.6 (1.6) 3.6 (1.6) 3.5 (1.5) 3.5 (1.5) 3.5 (1.5) 3.7 (1.5) 3.6 (1.5) Ͻ.001 Without CP 3.9 (1.6) 3.7 (1.6) 3.8 (1.6) 3.8 (1.6) 3.9 (1.6) 3.9 (1.6) 3.8 (1.6) 3.7 (1.6) Level of father’s education, mean (SD)c With CP 3.8 (1.6) 3.8 (1.5) 4.0 (1.7) 3.7 (1.6) 3.7 (1.6) 3.8 (1.6) 3.8 (1.6) 3.8 (1.6) Ͻ.001 Without CP 4.0 (1.7) 3.9 (1.6) 4.0 (1.7) 4.0 (1.7) 4.0 (1.7) 4.0 (1.7) 4.0 (1.6) 3.8 (1.6) Immigrant parentsd With CP 29 (1.5) 2 (1.7) 2 (1.1) 5 (1.4) 9 (1.9) 7 (1.7) 3 (1.3) 1 (1.1) .02 Without CP 39 135 (2.4) 2419 (3.9) 5512 (3.7) 9661 (2.9) 10 423 (2.2) 6765 (1.8) 3048 (1.7) 1307 (2.0) Abbreviations: CI, confidence interval; CP, cerebral palsy; RR, relative risk. aThe category includes gestational age from 43 weeks 0 days through 44 weeks 6 days. bP values for overall differences between infants with and without CP obtained by ␹2 tests, except for level of maternal and paternal education (t test). cEducation level was assessed on a national scale from 0 to 8 in which 0 resembles no education and 8 the highest degree at university level. dParents were considered immigrants if both parents were born outside of Norway.

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The question of causal interpreta- Labor and delivery complications are could indicate that CP is caused by tion has been a long-standing puzzle commonly found in infants subse- damage to the infant in the course of for CP in another important respect. quently diagnosed with CP. This delivery, but it could also mean that

Table 2. Birth and Neonatal Characteristics of the CP and Non-CP Cases Stratified by Gestational Age at Birth Weeks, No. (%) P Overall 37 38 39 40 41 42 Ն43a Valueb Birth weight, mean (SD), g With CP 3437 (556) 2908 (591) 3196 (493) 3350 (516) 3518 (531) 3564 (518) 3580 (542) 3609 (490) Ͻ.001 Without CP 3585 (480) 3148 (477) 3328 (450) 3488 (442) 3617 (449) 3711 (461) 3751 (477) 3695 (484) Head circumference, mean (SD), cm With CP 35.1 (1.7) 34.2 (1.8) 34.6 (1.5) 34.9 (1.6) 35.3 (1.7) 35.3 (1.6) 35.7 (1.8) 35.7 (1.8) Ͻ.001 Without CP 35.3 (1.5) 34.4 (1.6) 34.8 (1.5) 35.1 (1.4) 35.4 (1.4) 35.6 (1.4) 35.8 (1.4) 35.7 (1.5) Male sex With CP 1109 (57.2) 69 (56.1) 116 (60.1) 211 (56.1) 301 (61.9) 224 (53.7) 138 (55.6) 50 (52.6) Ͻ.001 Without CP 856 004 (50.9) 36 036 (56.2) 84 482 (54.7) 178 978 (52.5) 245 571 (50.2) 189 291 (49.3)89247 (49.1) 32 399 (49.0) Cesarean delivery With CP 279 (14.4) 34 (27.6) 42 (21.8) 49 (13.0) 58 (11.9) 41 (9.8) 37 (14.9) 18 (18.9) Ͻ.001 Without CP 120 793 (7.2) 9054 (14.1) 19 528 (12.6) 28 793 (8.4) 24 781 (5.1) 20 081 (5.2) 13 097 (7.2) 5459 (8.3) Forceps delivery With CP 76 (3.9) 3 (2.4) 6 (3.1) 10 (2.7) 22 (4.5) 14 (3.4) 11 (4.4) 10 (10.5) Ͻ.001 Without CP 39 773 (2.4) 1091 (1.7) 2644 (1.7) 6209 (1.8) 10 964 (2.2) 10 708 (2.8) 6031 (3.3) 2126 (3.2) Vacuum delivery With CP 130 (6.7) 2 (1.6) 10 (5.2) 26 (6.9) 26 (5.3) 34 (8.2) 20 (8.1) 12 (12.6) Ͻ.001 Without CP 65 923 (3.9) 1727 (2.7) 4150 (2.7) 9967 (2.9) 18 019 (3.7) 18 102 (4.7) 10 306 (5.7) 3652 (5.5) Breech or other malpresentations With CP 135 (7.0) 7 (5.7) 20 (10.4) 23 (6.1) 23 (4.7) 36 (8.6) 14 (5.6) 12 (12.6) Ͻ.001 Without CP 72 940 (4.3) 3801 (5.9) 8423 (5.5) 15 961 (4.7) 19 229 (3.9) 15 160 (3.9) 7574 (4.2) 2792 (4.2) Induction With CP 273 (14.1) 9 (7.3) 17 (8.8) 35 (9.3) 49 (10.1) 55 (13.2) 76 (30.6) 32 (33.7) Ͻ.001 Without CP 186 181 (11.1) 6710 (10.5) 13 575 (8.8) 23 915 (7.0) 37 362 (7.6) 43 004 (11.2)45980 (25.3) 15 365 (23.7) Apgar scores at 5 minc 0-3 With CP 80 (7.1) 3 (3.5) 10 (8.8) 11 (5.3) 22 (7.7) 23 (9.6) 9 (6.4) 2 (4.2) Ͻ.001 Without CP 945 (0.1) 76 (0.2) 85 (0.1) 164 (0.1) 236 (0.1) 221 (0.1) 112 (0.1) 51 (0.1) 4-6 With CP 134 (12.0) 12 (14.1) 10 (8.8) 21 (10.2) 27 (9.4) 33 (13.8) 22 (15.6) 9 (18.8) Ͻ.001 Without CP 5645 (0.5) 388 (0.9) 516 (0.5) 938 (0.4) 1354 (0.4) 1333 (0.5) 756 (0.6) 360 (0.9) Rupture of membranes Ն12 h before deliveryd With CP 14 (15.1) 8 (33.3) 1 (9.1) 2 (12.5) 1 (4.5) 2 (10.0) .05 Without CP 13 390 (9.1) 2784 (13.0) 2961 (10.1) 3490 (8.5) 2582 (7.9) 1573 (7.0) Meconium-stained amniotic fluidd With CP 29 (31.2) 6 (25.0) 4 (36.4) 3 (18.8) 8 (36.4) 8 (40.0) Ͻ.001 Without CP 25 624 (17.4) 1489 (7.0) 3363 (11.4) 7107 (17.3) 7583 (23.2) 6082 (27.2) Prolonged labord With CP 9 (9.7) 3 (12.5) 1 (9.1) 1 (6.3) 2 (9.1) 2 (10.0) .30 Without CP 10 175 (6.9) 908 (4.2) 1489 (5.1) 2717 (6.6) 2770 (8.5) 2291 (10.2) Neonate transferred to pediatric serviced With CP 39 (41.9) 9 (37.5) 3 (27.3) 6 (37.5) 9 (40.9) 12 (60.0) Ͻ.001 Without CP 7753 (5.3) 1861 (8.7) 1339 (4.6) 1713 (4.2) 1538 (4.7) 1302 (5.8) Abbreviation: CP, cerebral palsy. aThe category includes gestational age from 43 weeks and 0 days through 44 weeks and 6 days. bP values for overall differences between infants with and without CP obtained by ␹2 tests, except for birth weight and head circumference (t test). cApgar score reliably recorded in Medical Birth Registry from 1978. dInformation was available from a subcohort of 146 984 children (including 93 later registered with CP) born December 1998 through December 2001. Due to the small numbers, children with a gestational age of 37 and 38 weeks were grouped into 1 category as well as those with a gestational age of 42 through 44 weeks.

Downloaded from www.jama.com at University of Alabama-Birmingham on September 29, 2010 CEREBRAL PALSY AND TIMING OF BIRTH the prenatal factors leading to CP recording of gestational age or other 16,38 Figure 3. Adjusted Relative Risk of Cerebral cause problems of delivery. The study variables may have affected the Palsy by Gestational Age Measured by Last lower birth weight and head circum- results. However, when stratifying by Menstrual Period vs Ultrasound ference at birth among CP cases sug- time period, there was no evidence that Based on LMP gest that these children differ from the association of gestational age with 40 non-CP infants even before birth. As CP differed over time. 10 with most previous studies, our Neonatal mortality declined by 75% study has no possibility of discerning during the study period. Some chil- Adjusted 1.0 prenatal from perinatal or postnatal dren who survived with CP in more re- Relative Risk causes of CP. cent years might have died if they had 0.4 37 38 39 40 41 42 >42 been born in earlier years, which could Strengths and Weaknesses lead to an increase in severe cases of CP Based on ultrasound 40 A strength of this study is its popula- over time. What we observe, however, tion-based cohort design. This pro- is the opposite—the prevalence of CP 10 vides statistical power for gestational- has declined slightly over time. Fac- age–specific estimates of risk during the tors that have reduced neonatal mor- Adjusted 1.0 Relative Risk term and postterm periods, when risk tality may also have reduced the risk of 0.4 of CP is low. The study design also CP. 37 38 39 40 41 42 >42 avoids problems of selective participa- Gestational Age, wk Clinical Implications tion, detection bias, recall bias, and loss Relative risk of cerebral palsy (adjusted for year of to follow-up. Clinicians typically regard term birth, infant sex, maternal age, single motherhood, 12 mother and father’s level of education, and immi- We were able to adjust for possible births (37-41 weeks ) as low risk, grant status of the parents) related to gestational risk factors including maternal age, with the possibility of increased risk age in a subcohort of 139 976 individuals born from single motherhood, mother’s and fa- with postterm delivery.39 This stan- December 1998 through 2001. LMP indicates last menstrual period; errors bars indicate 95% confi- ther’s level of education, immigrant sta- dard definition of term does not cor- dence intervals. Reference category for both plots is tus of the parents, and infant sex. These respond well with the period of low- 40 weeks. factors made little difference to the est risk for CP in this study or with results. the weeks when most infants are it would be hasty to assume that inter- One notable weakness of the study born. Weeks 37 and 38 seem more to ventions on gestational age at delivery is the lack of any information on sub- resemble weeks 42 and 43, both in could reduce the occurrence of CP. types of CP. We are unable to deter- CP risk and in the general likelihood mine, for example, whether the risks of delivery, leaving 39 to 41 weeks as Author Contributions: Dr Moster had full access to with gestational age are more pro- the optimum time for delivery. all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data nounced for certain subtypes. Further- If the time of delivery affects CP analysis. more, by using a disability register to risk, then intervention at 40 weeks Study concept and design: Moster, Wilcox, Vollset, Markestad, Lie. identify CP, we may have missed in- might reduce CP risk, while elective Acquisition of data: Moster. formation on some of the mildest CP delivery at 37 or 38 weeks might Analysis and interpretation of data: Moster, Wilcox, Vollset, Markestad, Lie. cases, as suggested by an earlier vali- increase it. If infants prone to CP Drafting of the manuscript: Moster. dation study.15 The CP cases in the are disrupted in their delivery times, Critical revision of the manuscript for important present study may in general be more the prevalence of CP would be intellectual content: Moster, Wilcox, Vollset, Markestad, Lie. severe than if they had been identified unchanged regardless of time of deliv- Statistical analysis: Moster, Lie. by hospital or clinic records. ery. A definitive answer would require Administrative, technical, or material support: Moster. The exclusion of children who died a randomized clinical trial of deliver- Study supervision: Moster, Wilcox, Vollset, before 4 years of age could potentially ies at various gestational ages—an Markestad, Lie. Financial Disclosures: None reported. bias the results by excluding the most impractical option, given the very low Funding/Support: This research was supported in severe cases of CP. However, of the prevalence of CP. A clue might come part by the Intramural Research Program of the National Institutes of Health, National Institute of 7096 children who died before 4 years from the U-shaped risk of congenital Environmental Health Sciences; the Unger-Vetlesen of age, only 3 had a diagnosis of CP. Re- anomalies with gestational age, which Charitable Fund; The US-Norway Fulbright Founda- peated analyses after inclusion of all is definitely not causal. If the same tion; the Norwegian Society of Pediatricians; the University of Bergen; and the Research Council of children who died before the age of 4 occurs with CP, then a change in time Norway. years had no effect on the results. of delivery would have no influence Role of the Sponsors: The funding agencies had no role in the design and conduct of the study; in the col- Another possible difficulty is the ac- on a child’s underlying risk of CP. lection, analysis, and interpretation of the data; or in cumulation of births over such a long Until the biological mechanisms for the preparation, review, or approval of the manuscript. time interval (35 years). Changes in ob- these patterns of risk in term and Online-Only Material: The eTable and eFigures 1 and stetric practice, CP diagnosis, and the postterm births are better understood, 2 are available at http://www.jama.com.

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The original insight is most likely to come when ele- ments stored in different compartments of the mind drift into the open, jostle one another, and now and then form new combinations....[Ofcourse] the working out of ideas and insights requires persistent hard thinking.

— Eric Hoffer (1902-1983)

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